Dr. Charles Wood is seeking SERCA support to advance development as an independent investigator in comparative medicine. The career development plan will combine the unique resources of the Wake Forest University School of Medicine with expertise from international leaders in cancer research. The research plan will complement the candidate's current skills in pathology with a strong focus in molecular analyses of breast tissue. The overall research objective of this proposal is to evaluate the breast cancer risk profile of different postmenopausal hormone therapies and to investigate underlying mechanisms. Over 10 million postmenopausal women in the U.S. currently take hormone therapy (HT). The most common type of HT for women in the U.S. with a uterus is the combination of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA). Recent evidence indicates that the addition of MPA significantly increases the risk of breast cancer, and this has led to considerable uncertainty and concern regarding progestin use. A major question in women's health at this time is whether these adverse effects are specific to MPA or characteristic of all progestins. Given the diverse and in some cases opposing cellular actions of different progestin types, it is likely that these compounds have distinctive effects in the breast. In Phase 1 of this project we will use a surgically postmenopausal non-human primate model to compare the breast effects of MPA and natural progesterone (P4) when given with estradiol. We hypothesize that these progestins will have type-specific effects on proliferation, apoptosis, and estrogen metabolism in the breast and that P4 will have the most favorable profile. The aims of the project are as follows: (1) to determine progestin effects on breast proliferation and apoptosis; (2) to evaluate the glucocorticoid activities of MPA and P4 in relation to cell survival; and (3) to determine progestin effects on estrogen metabolism. In the second phase we will contrast the breast cancer risk profile of the optimal estrogen+progestin combination from Phase 1 with that of alternative hormone therapies. This work will have immediate public health relevance to postmenopausal women seeking the safest form of hormone therapy.